Medicinal benefits have been attributed to the cannabis plant for centuries. The primary bioactive constituent of cannabis is Δ9-tetrahydro-cannabinol (THC). The discovery of THC eventually led to the identification of two endogenous cannabinoid receptors responsible for its pharmacological actions, namely CB1 and CB2 (Goya et al., Exp. Opin. Ther. Patents, 2000, 10, 1529). These discoveries not only established the site of action of THC, but also inspired inquiries into the endogenous agonists of these receptors, or “endocannabinoids”. The first endocannabinoid identified was the fatty acid amide arachidonyl ethanolamide or anandamide (AEA). AEA itself elicits many of the pharmacological effects of exogenous cannabinoids (Piomelli et al., Nat. Rev. Neurosci., 2003, 4(11), 873).
The catabolism of AEA is primarily attributable to the integral membrane bound protein fatty acid amide hydrolase (FAAH), which hydrolyzes AEA to arachidonic acid and ethanolamine. FAAH was characterized in 1996 by Cravatt and co-workers (Cravatt et al., Nature, 1996, 384, 83). It was subsequently determined that FAAH is additionally responsible for the catabolism of a large number of important lipid signaling fatty acid amides including: another major endocannabinoid, 2-arachidonoylglycerol (2-AG) (Devane et al., Science, 1992, 258, 1946-1949); the sleep-inducing substance, oleamide (Cravatt et al., Science, 1995, 268, 1506); the appetite-suppressing agent, N-oleoylethanolamide (OEA) (Rodriguez de Fonesca, Nature, 2001, 414, 209); and the anti-inflammatory agent, palmitoylethanolamide (PEA) (Lambert et al., Curr. Med. Chem., 2002, 9(6), 663).
Small-molecule inhibitors of FAAH should elevate the concentrations of these endogenous signaling lipids and thereby produce their associated beneficial pharmacological effects. There have been some reports of the effects of various FAAH inhibitors in pre-clinical models.
In particular, two carbamate-based inhibitors of FAAH were reported to have analgesic properties in animal models. In rats, BMS-1 (see WO 02/087569), which has the structure shown below, was reported to have an analgesic effect in the spinal nerve ligation (Chung) model of neuropathic pain, and the Hargreaves test of acute thermal nociception. URB-597 was reported to have efficacy in the zero plus maze model of anxiety in rats, as well as analgesic efficacy in the rat hot plate and formalin tests (Kathuria et al., Nat. Med., 2003, 9(1), 76). The urea, 4-(3-Phenyl-[1,2,4]thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide, was found to be efficacious in both the spinal nerve ligation (Chung) model of neuropathic pain and the mild thermal injury model of acute burn injury pain (Karbarz et al., Anesth Analg., 2009, 108(1), 316-329). Other potent urea inhibitors of the FAAH enzyme have been reported (WO 06/074025). The sulfonylfluoride AM374 was also shown to significantly reduce spasticity in chronic relapsing experimental autoimmune encephalomyelitis (CREAE) mice, an animal model of multiple sclerosis (Baker et al., FASEB J., 2001, 15(2), 300).

In addition, the oxazolopyridine ketone OL-135 is reported to be a potent inhibitor of FAAH with analgesic activity in both the hot plate and tail immersion tests of thermal nociception in rats (WO 04/033652).

Results of research on the effects of certain exogenous cannabinoids has elucidated that a FAAH inhibitor may be useful for treating various conditions, diseases, disorders, or symptoms. These include pain, nausea/emesis, anorexia, spasticity, movement disorders, epilepsy and glaucoma. To date, approved therapeutic uses for cannabinoids include the relief of chemotherapy-induced nausea and emesis among patients with cancer and appetite enhancement in patients with HIV/AIDs who experience anorexia as a result of wasting syndrome. Two products are commercially available in some countries for these indications, namely, dronabinol (Marinol®) and nabilone.
Apart from the approved indications, a therapeutic field that has received much attention for cannabinoid use is analgesia, i.e., the treatment of pain. Five small randomized controlled trials showed that THC is superior to placebo, producing dose-related analgesia (Robson et al., Br. J. Psychiatry, 2001, 178, 107-115). Atlantic Pharmaceuticals is reported to be developing a synthetic cannabinoid, CT-3, a 1,1-dimethyl heptyl derivative of the carboxylic metabolite of tetrahydrocannabinol, as an orally active analgesic and anti-inflammatory agent. A pilot phase II trial in chronic neuropathic pain with CT-3 was reportedly initiated in Germany in May 2002.
A number of individuals with locomotor activity-related diseases, such as multiple sclerosis have claimed a benefit from cannabis for both disease-related pain and spasticity, with support from small controlled trials (Croxford et el., J. Neuroimmunol, 2008, 193, 120-9; Svendsen, Br. Med. J., 2004, 329, 253). Likewise, various victims of spinal cord injuries, such as paraplegia, have reported that their painful spasms are alleviated after smoking marijuana. A report showing that cannabinoids appear to control spasticity and tremor in the CREAE model of multiple sclerosis demonstrated that these effects are mediated by CB1 and CB2 receptors (Baker, Nature, 2000, 404, 84-87). Phase 3 clinical trials have been undertaken in multiple sclerosis and spinal cord injury patients with a narrow ratio mixture of tetrahydrocannabinol/cannabidiol (THC/CBD). It has been reported that FAAH knockout mice consistently recover to a better clinical score than wild type controls, and this improvement is not a result of anti-inflammatory activity, but rather may reflect some neuroprotection or remyelination promoting effect of lack of the enzyme (Webb et al, Neurosci Lett., 2008, vol. 439, 106-110).
Reports of small-scale controlled trials to investigate other potential commercial uses of cannabinoids have been made. Trials in volunteers have been reported to have confirmed that oral, injected, and smoked cannabinoids produced dose-related reductions in intraocular pressure (IOP) and therefore may relieve glaucoma symptoms. Ophthalmologists have prescribed cannabis for patients with glaucoma in whom other drugs have failed to adequately control intraocular pressure (Robson et al., 2001, supra).
Inhibition of FAAH using a small-molecule inhibitor may be advantageous compared to treatment with a direct-acting CB1 agonist. Administration of exogenous CB1 agonists may produce a range of responses, including reduced nociception, catalepsy, hypothermia, and increased feeding behavior. These four in particular are termed the “cannabinoid tetrad.” Experiments with FAAH−/− mice show reduced responses in tests of nociception, but did not show catalepsy, hypothermia, or increased feeding behavior (Cravatt et al., Proc. Natl. Acad. Sci. USA, 2001, 98(16), 9371). Fasting caused levels of AEA to increase in rat limbic forebrain, but not in other brain areas, providing evidence that stimulation of AEA biosynthesis may be anatomically regionalized to targeted CNS pathways (Kirkham et al., Br. J. Pharmacol., 2002, 136, 550). The finding that AEA increases are localized within the brain, rather than systemic, suggests that FAAH inhibition with a small molecule could enhance the actions of AEA and other fatty acid amides in tissue regions where synthesis and release of these signaling molecules is occurring in a given pathophysiological condition (Piomelli et al., 2003, supra).
In addition to the effects of a FAAH inhibitor on AEA and other endocannabinoids, inhibitors of FAAH's catabolism of other lipid mediators may be used in treating certain other therapeutic indications. For example, PEA has demonstrated biological effects in animal models of inflammation (Holt et al., Br. J. Pharmacol., 2005, 146, 467-476), immunosuppression, analgesia, and neuroprotection (Ueda et al., J. Biol. Chem., 2001, 276(38), 35552). Oleamide, another substrate of FAAH, induces sleep (Boger et al., Proc. Natl. Acad. Sci. USA, 2000, 97(10), 5044; Mendelson et al., Neuropsychopharmacology, 2001, 25, S36). Inhibition of FAAH has also been implicated in cognition (Varvel et al., J. Pharmacol. Exp. Ther., 2006, 317(1), 251-257) and depression (Gobbi et al., Proc. Natl. Acad. Sci. USA, 2005, 102(51), 18620-18625).
Two additional indications for FAAH are supported by recent data indicating that FAAH substrate activated receptors are important in energy metabolism, and in bone homeostasis (Overton et al., Br. J. Pharmacol., 2008, 153 Suppl 1, S76-81; and Plutzky et al., Diab. Vasc. Dis. Res., 2007, 4 Suppl 3, S12-4). It has been shown that one of the previously mentioned lipid signaling fatty acid amides catabolized by FAAH, OEA, is one of the most active agonists of the recently de-orphanised GPCR 119 (GPR119) (also termed glucose-dependent insulinotropic receptor). This receptor is expressed predominantly in the pancreas in humans and activation improves glucose homeostasis via glucose-dependent insulin release in pancreatic beta-cells. GPR119 agonists can suppress glucose excursions when administered during oral glucose tolerance tests, and OEA has also been shown independently to regulate food intake and body weight gain when administered to rodents, indicating a probable benefit in energy metabolism disorders, such as insulin resistance and diabetes. The FAAH substrate PEA is an agonist at the PPARα receptor. Evidence from surrogate markers in human studies with the PPARα agonist fenofibrate is supportive of the concept that PPARα agonism offers the potential for inducing a coordinated PPARα response that may improve dyslipidaemia, repress inflammation and limit atherosclerosis in patients with the metabolic syndrome or type 2 diabetes. Anandamide is an agonist at the PPARγ receptor. Anandamide treatment induces 3T3-L1 differentiation into adipocytes, as well as triglyceride droplet accumulation and expression of adiponectin (Bouaboula et al., E. J. Pharmacol., 2005, 517, 174-181). Low dose cannabinoid therapy has been shown to reduce atherosclerosis in mice, further suggesting a therapeutic benefit of FAAH inhibition in dyslipidemia, liver steatosis, steatohepatitis, obesity, and metabolic syndrome (Steffens et al., Nature, 2005, 434, 782-6).
Osteoporosis is one of the most common degenerative diseases. It is characterized by reduced bone mineral density (BMD) with an increased risk for bone fractures. CB2-deficient mice have a markedly accelerated age-related trabecular bone loss and cortical expansion. A CB2-selective agonist enhances endocortical osteoblast number and activity and restrains trabecular osteoclastogenesis and attenuates ovariectomy-induced bone loss (Ofek et al., Proc. Natl. Acad. Sci. U.S.A., 2006, 103, 696-701). There is a substantial genetic contribution to BMD, although the genetic factors involved in the pathogenesis of human osteoporosis are largely unknown. The applicability to human BMD is suggested by genetic studies in which a significant association of single polymorphisms and haplotypes was found encompassing the CNR2 gene on human chromosome 1p36, demonstrating a role for the peripherally expressed CB2 receptor in the etiology of osteoporosis (Karsak et al., Hum. Mol. Genet, 2005, 14, 3389-96).
Thus, small-molecule FAAH inhibitors should be useful in treating pain of various etiologies, anxiety, multiple sclerosis and other movement disorders, nausea/emesis, eating disorders, epilepsy, glaucoma, inflammation, immunosuppression, neuroprotection, depression, cognition enhancement, and sleep disorders, and potentially with fewer side effects than treatment with an exogenous cannabinoid.
A number of heteroaryl-substituted ureas have been reported in various publications. Certain piperazinyl and piperidinyl compounds as FAAH modulators are described in Intl. Patent Appl. No. WO 2006/074025, Intl. Patent Appl. Ser. No. PCT/US2009/065757, Intl. Patent Appl. Ser. No. PCT/US2009/065752, U.S. Appl. Publ. No. US 2009/0062294, and U.S. provisional Appl. Ser. No. 61/263,477. Certain piperazine-1-carboxamide and piperidine-1-carboxamide derivatives are described in Intl. Patent Appl. No. WO 2008/023720. Certain aryloxobutylpiperidines, aryloxobutylpyrrolidines, and aryloxobutylpiperazines are described in Intl. Patent Appl. No. WO 2001/005763. Certain piperidine derivatives are reported in Intl. Patent Appl. No. WO 99/50247. Certain piperazine derivatives are described in Intl. Patent Appl. No. WO 99/42107. Certain N-aralkylpiperazines are described in Intl. Patent Appl. No. WO 98/37077. Certain aryl-substituted heterocyclic urea derivatives are described in U.S. provisional Appl. No. 61/184,606. However, there remains a desire for potent FAAH modulators with suitable pharmaceutical properties.
The features and advantages of the present invention are apparent to one of ordinary skill in the art. Based upon this disclosure, including the summary, detailed description, background, examples, and claims, one of ordinary skill in the art will be able to make modifications and adaptations to various conditions and usages. Publications described herein are incorporated by reference in their entirety.